Decrease in p3‐Alcβ37 and p3‐Alcβ40, products of Alcadein β generated by γ‐secretase cleavages, in aged monkeys and patients with Alzheimer's disease

Alzheimer's and Dementia: Translational Research and Clinical Interventions - Tập 5 - Trang 740-750 - 2019
Saori Hata1, Chiori Omori1,2, Ayano Kimura1, Haruka Saito1, Nobuyuki Kimura3,4, Veer Gupta5,6,7, Steve Pedrini6,7, Eugene Hone6,7, Pratishtha Chatterjee8, Kevin Taddei6, Kensaku Kasuga9, Takeshi Ikeuchi9, Masaaki Waragai10, Masaki Nishimura11, Anqi Hu1, Tadashi Nakaya1, Laurent Meijer12, Masahiro Maeda13, Tohru Yamamoto1,14, Colin L. Masters15
1Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
2Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Japan
3Section of Cell Biology and Pathology, Department of Alzheimer's Disease Research, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Japan
4Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Tsukuba, Japan
5Centre of Excellence for Alzheimer's Disease Research and Care, Sir James McCusker Alzheimer's Disease Research Unit, Edith Cowan University, Joodalup, WA, Australia
6School of Medical and Health Sciences, Edith Cowan University Joondalup, WA, Australia
7Co-operative Research Centre for Mental Health, Carlton, VIC, Australia
8Department of Biomedical Sciences, Faculty of Medical and Health Sciences, Macquarie University, Sydney, NSW, Australia
9Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan
10Department of Neurology, Higashi Matsudo Municipal Hospital, Matsudo, Japan
11Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Japan
12ManRos Therapeutics, Centre de Perharidy, Roscoff, Bretagne, France
13Immuno-Biological Laboratories Co., Ltd. (IBL), Fujioka, Japan
14Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa, Japan
15Neurodegeneration Division, The Florey Institute, The University of Melbourne, Parkville, VIC, Australia

Tóm tắt

AbstractIntroductionNeuronal p3‐Alcβ peptides are generated from the precursor protein Alcadein β (Alcβ) through cleavage by α‐ and γ‐secretases of the amyloid β (Aβ) protein precursor (APP). To reveal whether p3‐Alcβ is involved in Alzheimer's disease (AD) contributes for the development of novel therapy and/or drug targets.MethodsWe developed new sandwich enzyme‐linked immunosorbent assay (sELISA) systems to quantitate levels of p3‐Alcβ in the cerebrospinal fluid (CSF).ResultsIn monkeys, CSF p3‐Alcβ decreases with age, and the aging is also accompanied by decreased brain expression of Alcβ. In humans, CSF p3‐Alcβ levels decrease to a greater extent in those with AD than in age‐matched controls. Subjects carrying presenilin gene mutations show a significantly lower CSF p3‐Alcβ level. A cell study with an inverse modulator of γ‐secretase remarkably reduces the generation of p3‐Alcβ37 while increasing the production of Aβ42.DiscussionAging decreases the generation of p3‐Alcβ, and further significant decrease of p3‐Alcβ caused by aberrant γ‐secretase activity may accelerate pathogenesis in AD.

Tài liệu tham khảo

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Alzheimer's and Dementia: Translational Research and Clinical Interventions

Tập 5

740-750

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